Sudden Death in Infants Could Have a Genetic Basis

Sudden Infant Death Syndrome (SIDS), paediatric mortality without established causes, accounts for 10% of infant deaths in the US. Typically, it occurs in infants less than a year old or young children up to 3 years. Since SIDS does not have any symptoms or clinical manifestations, there is not a lot of data available to investigate the cause of death. A recent research article published in Genetics in Medicine unravels a genetic basis for Sudden Unexpected Death in Pediatrics (SUDP), interchangeably used with SIDS.

The study was part of the Robert’s Program at Boston’s Children’s Hospital (BHC). It investigates the genetic basis of SUPD since most children with SIDS die before the age of one and do not have a long clinical and medical history. Therefore, this study investigates a uniquely unstudied population from a genetics perspective and introduces a level of phenotyping not previously seen.

Biology behind SIDS

In an interview discussion with GeneOnline’s CEO, Thomas Huang, the leading authors of the report Dr. Hyun Yong Koh (Postdoctoral fellow, BCH), Dr. Alireza Haghighi (Founding Director of the International Center for Genetic Disease, and Assistant Professor of Medicine, Brigham and Women’s Hospital, Harvard Medical School) and Dr. Richard Goldstein (Director of Robert’s Program, and Assistant Professor of Pediatrics, Boston Children’s Hospital, Harvard Medical School) spoke of their motivations, hypotheses and significant findings from this curiosity-based, exploratory research. 

Dr. Alireza Haghighi

Dr. Haghighi put the study in perspective by explaining how the study design allowed them to expand the range of questions to be asked about SIDS, since most available data for SIDS patients are analysed in retrospect. With a multidisciplinary approach to including genotype and phenotype analysis from patients, the study allows identifying risk factors that could inform counselling and screening for siblings. “We provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death,” he said.

Dr. Richard Goldstein

Dr. Goldstein said that a sizable genomic cohort allowed them to answer the fundamental question of SIDS being a sleep accident or if there is some underlying biology using newly developed analysis modalities such as the burden analysis.  

Deriving Biologically Valuable Information from DNA Codes

Analysing exome sequencing data from over 350 infants who succumbed to SIDS over the last decade, and a subset of parents, the authors generated a list of 294 candidate genes with variants. Further analysis identified 109 rare variants, of which 37 could be defined as pathogenic and likely pathogenic according to the American College of Medical Genetics. Of them, 13 were associated with neurological disease, 18 with cardiac disease and 6 with systemic diseases.  

To understand genetic and phenotypic linkages, authors corroborated variant analysis in a subset of patients and parents with detailed family history to identify new variants for sudden death in paediatrics. “This unbiased trio/quad-approach to analyse SIDS is innovative. It helps to identify and interpret variants. If you identify a variant that is inherited from one parent and hypothesize that the variant causes that condition, but then you identify the same variant in the parent, you would think that it’s unlikely that that variant caused the condition,” Haghighi noted.

Co-author Dr. Koh explained the methodology to decide on the pathogenicity of a variant which involved discussing each case and their variant candidates with specialists from endocrinology, neurology, pathology, cardiology etc to understand how each of the genetic determinants could have contributed to SIDS. Speaking of the multidisciplinary approach to the analysis of genetic data, he said “genes associated with epilepsy and cardiac diseases are frequently identified, even when the phenotype has not yet shown itself.

Dr. Hyun Yong Koh

Through this genetic work, we can establish evidence for these associations. Many of our results rely not only on academic findings but on the patients’ families as well as clinical accomplishments. This is a good example of precision medicine.” The next step would be to identify the mechanism by which these genes result in SIDS. Dr. Koh emphasized the need of functional analysis using cell line/animal models to understand the clinical manifestation of the new variants.

As a proof-of-concept, this study shows a possible way of uncovering the reason for SIDS which is a very important step to help families to understand what happened, cope with loss and identify risk factors for other family members. 

The next step would be to design diagnostics and therapeutics. The first step towards understanding of what are the factors that could have contributed to death would be to develop and validate hypotheses with more collaborative work. Ultimately, this kind of population-level studies can identify risk factors for surveillance and possible areas of intervention.  

Author

Sahana Shankar